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The view that interacting with nature enhances mental wellbeing is commonplace, despite a dearth of evidence or even agreed definitions of 'nature'. The aim of this review was to systematically appraise the evidence for associations between greenspace and mental wellbeing, stratified by the different ways in which greenspace has been conceptualised in quantitative research. We undertook a comprehensive database search and thorough screening of articles which included a measure of greenspace and validated mental wellbeing tool, to capture aspects of hedonic and/or eudaimonic wellbeing. Quality and risk of bias in research were assessed to create grades of evidence. We undertook detailed narrative synthesis of the 50 studies which met the review inclusion criteria, as methodological heterogeneity precluded meta-analysis. Results of a quality assessment and narrative synthesis suggest associations between different greenspace characteristics and mental wellbeing. We identified six ways in which greenspace was conceptualised and measured: (i) amount of local-area greenspace; (ii) greenspace type; (iii) visits to greenspace; (iv) views of greenspace; (v) greenspace accessibility; and (vi) self-reported connection to nature. There was adequate evidence for associations between the amount of local-area greenspace and life satisfaction (hedonic wellbeing), but not personal flourishing (eudaimonic wellbeing). Evidence for associations between mental wellbeing and visits to greenspace, accessibility, and types of greenspace was limited. There was inadequate evidence for associations with views of greenspace and connectedness to nature. Several studies reported variation in associations between greenspace and wellbeing by life course stage, gender, levels of physically activity or attitudes to nature. Greenspace has positive associations with mental wellbeing (particularly hedonic wellbeing), but the evidence is not currently sufficient or specific enough to guide planning decisions. Further studies are needed, based on dynamic measures of greenspace, reflecting access and uses of greenspace, and measures of both eudaimonic and hedonic mental wellbeing.

Background With urbanisation increasing, it is important to understand how to design changing environments to promote mental wellbeing. Evidence suggests that local-area proportions of green space may be associated with happiness and life satisfaction; however, the available evidence on such associations with more broadly defined mental wellbeing in still very scarce. This study aimed to establish whether the amount of neighbourhood green space was associated with mental wellbeing. Methods Data were drawn from Understanding Society , a national survey of 30,900 individuals across 11,096 Census Lower-Layer Super Output Areas (LSOAs) in England, over the period 2009–2010. Measures included the multi-dimensional Warwick-Edinburgh Mental Well-Being Scale (SWEMWBS) and LSOA proportion of green space, which was derived from the General Land Use Database (GLUD), and were analysed using linear regression, while controlling for individual, household and area-level factors. Results Those living in areas with greater proportions of green space had significantly higher mental wellbeing scores in unadjusted analyses (an expected increase of 0.17 points ( 95% CI 0.11, 0.23) in the SWEMWBS score for a standard deviation increase of green space). However, after adjustment for confounding by respondent sociodemographic characteristics and urban/rural location, the association was attenuated to the null (regression coefficient B  = − 0.01, 95% CI -0.08, 0.05, p  = 0.712). Conclusions While the green space in an individual’s local area has been shown through other research to be related to aspects of mental health such as happiness and life satisfaction, the association with multidimensional mental wellbeing is much less clear from our results. While we did not find a statistically significant association between the amount of green space in residents’ local areas and mental wellbeing, further research is needed to understand whether other features of green space, such as accessibility, aesthetics or use, are important for mental wellbeing.

Volunteered Geographical Information (VGI) and social media can provide information about real-time perceptions, attitudes and behaviours in urban green space (UGS). This paper reviews the use of VGI and social media data in research examining UGS. The current state of the art is described through the analysis of 177 papers to (1) summarise the characteristics and usage of data from different platforms, (2) provide an overview of the research topics using such data sources, and (3) characterise the research approaches based on data pre-processing, data quality assessment and improvement, data analysis and modelling. A number of important limitations and priorities for future research are identified. The limitations include issues of data acquisition and representativeness, data quality, as well as differences across social media platforms in different study areas such as urban and rural areas. The research priorities include a focus on investigating factors related to physical activities in UGS areas, urban park use and accessibility, the use of data from multiple sources and, where appropriate, making more effective use of personal information. In addition, analysis approaches can be extended to examine the network suggested by social media posts that are shared, re-posted or reacted to and by being combined with textual, image and geographical data to extract more representative information for UGS analysis.

This thesis aimed to deepen understanding of the potential health benefits of urban greenspace, by identifying associations between different greenspace characteristics and mental wellbeing. A systematic literature review revealed that, while local area greenspace is adequately associated with life satisfaction, evidence for other characterisations of greenspace (type, accessibility, etc) is less sufficient. Although findings are currently not specific enough to guide planning decisions, there is a need to examine multidimensional wellbeing measures and greenspace in detail. A first study of local area greenspace and mental wellbeing in England, using data from 31,000 individuals in the UK Household Longitudinal Study survey and greenspace information (Generalised Land Use Database), found that Ordinary Least Squares associations between local prevalence of greenspace and multidimensional wellbeing could not be detected at census level, perhaps due to the imposition of arbitrary boundaries. More detailed post code-level data was obtained for 25,000 London residents completing the Annual Population Survey 2012-2015, with greenspace shapefiles from the Greenspace Information for Greater London group. The amount of greenspace within a 300m buffer of individuals homes was positively and significantly associated with hedonic and eudaimonic wellbeing. Geographically Weighted Regression models, addressing spatial clusters within the data, revealed slight variation in the strength of these associations across the study space. The final study, which characterised greenspace by type and accessibility on foot, found natural greenspace to be positively associated with hedonic wellbeing, but not eudaimonic wellbeing; associations with other types of greenspace were not significant. Spatial Error models allowed second-order processes within the structure of the data to be captured. These contributions are the first to examine nature planning recommendations for potential associations with mental wellbeing, expanding the current knowledge of greenspace design. Informed design should consider both the characteristics of the greenspace and local residents, to benefit the mental wellbeing of individuals and society as a whole.

BackgroundCharcot–Marie–Tooth disease (CMT) is a clinically and genetically heterogeneous group of diseases with approximately 45 different causative genes described. The aims of this study were to determine the frequency of different genes in a large cohort of patients with CMT and devise guidelines for genetic testing in practice.MethodsThe genes known to cause CMT were sequenced in 1607 patients with CMT (425 patients attending an inherited neuropathy clinic and 1182 patients whose DNA was sent to the authors for genetic testing) to determine the proportion of different subtypes in a UK population.ResultsA molecular diagnosis was achieved in 62.6% of patients with CMT attending the inherited neuropathy clinic; in 80.4% of patients with CMT1 (demyelinating CMT) and in 25.2% of those with CMT2 (axonal CMT). Mutations or rearrangements in PMP22, GJB1, MPZ and MFN2 accounted for over 90% of the molecular diagnoses while mutations in all other genes tested were rare.ConclusionFour commonly available genes account for over 90% of all CMT molecular diagnoses; a diagnostic algorithm is proposed based on these results for use in clinical practice. Any patient with CMT without a mutation in these four genes or with an unusual phenotype should be considered for referral for an expert opinion to maximise the chance of reaching a molecular diagnosis.

This article examines how imagined audiences and impression management strategies shape COVID-19 health information sharing practices on social media and considers the implications of this for combatting the spread of misinformation online. In an interview study with 27 Canadian adults, participants were shown two infographics about masks and vaccines produced by the World Health Organization (WHO) and asked whether or not they would share these on social media. We find that interviewees’ willingness to share the WHO infographics is negotiated against their mental perception of the online audience, which is conceptualized in three distinct ways. First, interviewees who would not share the infographics frequently describe a self-similar audience of peers that are “in the know” about COVID-19; second, those who might share the infographics conjure a specific and contextual audience who “needs” the information; and finally, those who said they would share the infographics most frequently conjure an abstract audience of “the public” or “my community” to explain that decision. Implications of these sharing behaviors for combatting the spread of misinformation are discussed.

Hereditary spastic paraplegia (HSP) is a group of heterogeneous inherited degenerative disorders characterized by lower limb spasticity. Fifty percent of HSP patients remain yet genetically undiagnosed. The 100,000 Genomes Project (100KGP) is a large UK-wide initiative to provide genetic diagnosis to previously undiagnosed patients and families with rare conditions. Over 400 HSP families were recruited to the 100KGP. In order to obtain genetic diagnoses, gene-based burden testing was carried out for rare, predicted pathogenic variants using candidate variants from the Exomiser analysis of the genome sequencing data. A significant gene-disease association was identified for UBAP1 and HSP. Three protein truncating variants were identified in 13 patients from 7 families. All patients presented with juvenile form of pure HSP, with median age at onset 10 years, showing autosomal dominant inheritance or de novo occurrence. Additional clinical features included parkinsonism and learning difficulties, but their association with UBAP1 needs to be established.

Background Targeting RAS mutant (MT) colorectal cancer (CRC) remains a difficult challenge, mainly due to the pervasiveness of RAS/MEK-mediated feedback loops. Preclinical studies identified MET/STAT3 as an important mediator of resistance to KRAS-MEK1/2 blockade in RAS MT CRC. This dose escalation/expansion study assessed safety and initial efficacy of the MEK1/2 inhibitor binimetinib with MET inhibitor crizotinib in RAS MT advanced CRC patients. Methods In the dose escalation phase, patients with advanced solid tumours received binimetinib with crizotinib, using a rolling- 6 design to determine the maximum tolerable dose (MTD) and safety/tolerability. A subsequent dose expansion in RAS MT CRC patients assessed treatment response. Blood samples for pharmacokinetics, MET biomarker and ctDNA analyses, and skin/tumour biopsies for pharmacodynamics, c-MET immunohistochemistry (IHC), MET in situ hybridisation (ISH) and MET DNA-ISH analyses were collected. Results Twenty patients were recruited in 3 cohorts in the dose escalation. The MTD was binimetinib 30 mg B.D, days 1–21 every 28 days, with crizotinib 250 mg O.D continuously. Dose-limiting toxicities included grade ≥ 3 transaminitis, creatinine phosphokinase increases and fatigue. Thirty-six RAS MT metastatic CRC patients were enrolled in the dose expansion. Pharmacokinetic and pharmacodynamic parameters showed evidence of target engagement. Across the entire study, the most frequent treatment-related adverse events (TR-AE) were rash (80.4%), fatigue (53.4%) and diarrhoea (51.8%) with grade ≥ 3 TR-AE occurring in 44.6%. Best clinical response within the RAS MT CRC cohort was stable disease in seven patients (24%). Tumour MET super-expression (IHC H-score > 180 and MET ISH + 3) was observed in 7 patients (24.1%), with MET -amplification only present in 1 of these patients. This patient discontinued treatment early during cycle 1 due to toxicity. Patients with high baseline  RAS MT allele frequency had a significant shorter median overall survival compared with that seen for patients with low baseline  KRAS MT allele frequency. Conclusions Combination binimetinib/crizotinib showed a poor tolerability with no objective responses observed in RAS MT advanced CRC patients. EudraCT-Number: 2014–000463 - 40 (20/06/2014: A Sequential Phase I study of MEK1/2 inhibitors PD- 0325901 or Binimetinib combined with cMET inhibitor Crizotinib in RAS Mutant and RAS Wild Type with aberrant c-MET).

AbstractObjectiveTo determine whether whole genome sequencing can be used to define the molecular basis of suspected mitochondrial disease.DesignCohort study.SettingNational Health Service, England, including secondary and tertiary care.Participants345 patients with suspected mitochondrial disorders recruited to the 100 000 Genomes Project in England between 2015 and 2018.InterventionShort read whole genome sequencing was performed. Nuclear variants were prioritised on the basis of gene panels chosen according to phenotypes, ClinVar pathogenic/likely pathogenic variants, and the top 10 prioritised variants from Exomiser. Mitochondrial DNA variants were called using an in-house pipeline and compared with a list of pathogenic variants. Copy number variants and short tandem repeats for 13 neurological disorders were also analysed. American College of Medical Genetics guidelines were followed for classification of variants.Main outcome measureDefinite or probable genetic diagnosis.ResultsA definite or probable genetic diagnosis was identified in 98/319 (31%) families, with an additional 6 (2%) possible diagnoses. Fourteen of the diagnoses (4% of the 319 families) explained only part of the clinical features. A total of 95 different genes were implicated. Of 104 families given a diagnosis, 39 (38%) had a mitochondrial diagnosis and 65 (63%) had a non-mitochondrial diagnosis.ConclusionWhole genome sequencing is a useful diagnostic test in patients with suspected mitochondrial disorders, yielding a diagnosis in a further 31% after exclusion of common causes. Most diagnoses were non-mitochondrial disorders and included developmental disorders with intellectual disability, epileptic encephalopathies, other metabolic disorders, cardiomyopathies, and leukodystrophies. These would have been missed if a targeted approach was taken, and some have specific treatments.

Mutations in the gene encoding the F-box domain–containing protein Fbxo7 are genetically associated to an autosomal recessive form of early-onset Parkinson's disease of similar severity to those caused by Parkinson's disease–linked mutations in the genes for the mitochondrial kinase PINK1 or the E3 ubiquitin ligase Parkin. Burchell et al . show that Fbxo7 acts in a common cellular and molecular pathway with Parkin and PINK1 in autophagic clearance of mitochondria in response to mitochondrial depolarization and damage. Compelling evidence indicates that two autosomal recessive Parkinson's disease genes, PINK1 ( PARK6 ) and Parkin ( PARK2 ), cooperate to mediate the autophagic clearance of damaged mitochondria (mitophagy). Mutations in the F-box domain–containing protein Fbxo7 (encoded by PARK15 ) also cause early-onset autosomal recessive Parkinson's disease, by an unknown mechanism. Here we show that Fbxo7 participates in mitochondrial maintenance through direct interaction with PINK1 and Parkin and acts in Parkin-mediated mitophagy. Cells with reduced Fbxo7 expression showed deficiencies in translocation of Parkin to mitochondria, ubiquitination of mitofusin 1 and mitophagy. In Drosophila , ectopic overexpression of Fbxo7 rescued loss of Parkin, supporting a functional relationship between the two proteins. Parkinson's disease–causing mutations in Fbxo7 interfered with this process, emphasizing the importance of mitochondrial dysfunction in Parkinson's disease pathogenesis.